The pharmaceutical antibiotic composition comprising ceftolozane and tazobactam in a 2:1 weight ratio of ceftolozane active to tazobactam active (“CXA-201”) displays potent antibacterial activity, including antibiotic activity against infections caused by many Gram-negative pathogens such as Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli), Klebsiella pneumonia (K. pneumonia). In particular, CXA-201 is a pharmaceutical composition useful for intravenous administration for the treatment of complicated intra-abdominal infections and/or complicated urinary tract infections, and is being evaluated for treatment of pneumonia.
Ceftolozane is a cephalosporin antibacterial agent, also referred to as CXA-101, FR264205, or by chemical names such as (6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-({(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-{3-amino-4-[3-(2-aminoethyl)ureido]-2-methyl-1-pyrazolio}methyl-3-cephem-4-carboxylate. The antibacterial activity of ceftolozane is believed to result from its interaction with penicillin binding proteins (PBPs) to inhibit the biosynthesis of the bacterial cell wall which acts to stop bacterial replication. Ceftolozane sulfate is a pharmaceutically acceptable ceftolozane salt of formula (I) that can be formulated for intravenous administration or infusion.

In CXA-201, ceftolozane is combined with the β-lactamase inhibitor (“BLI”) tazobactam. Tazobactam is a BLI against Class A and some Class C β-lactamases, with well-established in vitro and in vivo efficacy in combination with active β-lactam antibiotics. Tazobactam can be combined with ceftolozane as a free acid tazobactam form of formula (II).

Pharmaceutical compositions comprising one or more drug substances can be prepared by lyophilization of a solution containing the drug substance(s). Lyophilization is a process of freeze-drying in which water is sublimed from a frozen solution of one or more solutes. Specific methods of lyophilization are described in Remington's Pharmaceutical Sciences, Chapter 84, page 1565, Eighteenth Edition, A. R. Gennaro, (Mack Publishing Co., Easton, Pa., 1990). It has now been found and reported herein that compositions formed by lyophilizing ceftolozane and tazobactam through co-lyophilization, (i.e., the ceftolozane and tazobactam were combined and lyophilized together in Example 3, as opposed to separately) resulted in the formation of significant amounts of an undesired by-product represented by formula (III) (See Example 5 and the results reported in Tables 5 and 6 in FIGS. 7A and 7B).

Therefore, there remains a need for compositions comprising ceftolozane and/or tazobactam with reduced or even undectable amounts (e.g., less than about 0.03% by high performance liquid chromatography, or “HPLC”) of the compound of formula (III) and methods for manufacturing these compositions.